ES2331643T3 - TREATMENT OF DISORDERS ASSOCIATED WITH LFA-1 WITH GROWING DOSE OF ANTIGONIST OF LFA-1. - Google Patents

Abstract

A method is provided for reducing the occurrence of fever, headache, nausea and/or vomiting associated with administration of a therapeutic compound to a mammal in need thereof, comprising administering to the mammal a first conditioning dose of a non-target cell depleting compound which binds to a cell surface receptor on a target mammalian cell; and administering a second therapeutic dose of the compound, wherein the second dose is higher than the first dose.

Description

Treatment of disorders associated with LFA-1 with increasing doses of antagonist of LFA-1

Background Discussion

The administration of many therapeutic agents quickly induces adverse side effects, or events, which include, but are not limited to, fever, headache, nausea, vomiting, breathing difficulties and changes in tension arterial. These adverse events limit the amount that it can be administered of a drug or therapeutic compound, which at its instead limits the therapeutic efficacy that could be achieved with doses older drug. There is a continuing need to develop techniques that limit the toxicity of higher doses of drug so that therapeutic efficacy can be improved. This need it exists for both polypeptide compounds and not polypeptide

Antibodies are a type of compound polypeptide for those that frequently occur adverse events with administration that limit the dose of the compound that can be administered. A compound associated with adverse side effects is the murine monoclonal antibody OKT3 OKT3 binds to the CD3 protein complex that is associated to the T cell receptor (TCR) found on the surface of all T lymphocytes. Administration of OKT3 to humans quickly reduces the number of circulating T cells (by example, OKT3 is a compound that destroys cells) and reduces amount of TCR on the surface of the cell found on the remaining T cells (Cosimi et al. 1981 N Engl J Med, 305 (6), 308-314). The effects OKT3 immunosuppressants have been therapeutically useful in the renal transplant rejection treatment (Goldstein & Group 1985 M Engl J Med, 313 (6), 337-342). Without However, the administration of OKT3 induces several effects Adverse side effects that include fever, chills, nausea, vomiting and chest tightness It is believed that these side effects they are produced by the release of cytokines from T cells due to activation induced by OKT3 (Abramowicz et al. 1989 Transplantation 47 (4), 606-608) and the complement activation (Raasveld et al. 1993 Kidney International, 43, 1140-1149).

Several strategies have been developed to reduce side effects induced by OKT3. It has been shown that anti-inflammatory steroids attenuate the release of OKT3-induced cytokines (Goldman et al. 1989 Lancet, ii (8666), 802) (Chatenoud et al. 1990 Transplantation. 49 (4), 697-702) and indomethacin may reduce the feverish response (First, Schroeder, Hariharan, Alexander & Weiskittel, 1992 Transplantation, 53. (I). 91-94). A usual dose of 5 mg of OKT3 administered as an infusion of 2 hours instead of the usual bolus injection was better tolerated and reduced complement activation, but not the release of cytokines (ten Berge, Buysmann, van Diepen, Surachno & Hack, 1996 Transplant Proc. 28 (6), 3217-3220). The adverse events induced by OKT3 are the most significant after the first dose. While the dose initial (usually 5 mg) induces the release of cytokines and Activates the complement, also eliminates the target T cells. With fewer T cells and a reduced TCR density than are left, subsequent doses of OKT3 induce less cytokine release (Chatenoud et al. 1989 N Engl J Med, 320 (21), 1420-1421). One group found that after four daily dose of 5 mg, the dosage could be increased with safety at 10, 15 and 25 mg for the next 3 days (Woodle and cabbage. 1996 Clin Transplantation, 10,389-395).

Adverse events have also been associated with the initial administration of monoclonal antibodies directed to other cell surface molecules. A humanized anti-CD4 monoclonal antibody induced fever, chills, hypotension and chest tightness when administered intravenously to patients with psoriasis and rheumatoid arthritis (Isaacs et al. 1997 Clin Exp Immunol, 110, 158-166). This treatment modulated by decrease the expression of CD4 and produced a reduction in the number of T cells positive for circulating CD4, but it was not completely destructive. Bispecific antibodies were shown to interact with the CD64 molecule, a receptor for the immunoglobulin constant region (Fc gamma RI) and tumor-associated molecules (epidermal growth factor receptor MDX-447, or HER2 / neu MDX-H210) they produced flu-like symptoms such as fever and chills after the first dose (Cumow, 1997, Cancer Immunol Immunother, 45, 210-215). Similar to the effect of OKT3 on T cells, these antibodies produced a decrease in the number of monocytes in circulation, expressing CD64, and stimulated increases in plasma cytokines. A single dose of another monoclonal antibody directed at CD64 (MDX-33) modulated by decreasing the expression of CD64 in monocytes and also produced chills, fever, headache and muscle aches.
beef.

The interaction of T lymphocytes with cells antigen presenters (CPA) is one of the initial stages in the activation of an immune response to what is perceived by the immune system as a xenoantigen. Although it has focused much attention on the primary interaction of the recipient of T cells with the MHC antigen in the CPA, several others cell surface components also participate in the T cell activation. These pairs of ligands located on The surface of the T cell and the CPA include: LFA-1 / ICAM-1 (also ICAM-2 and ICAM-3), CD28 / B7, CD2 / LFA-3, CD4 / MHC class 11 and CD8 / MHC class 1. The interference with the binding of any of these ligand pairs (for example, with the use of binding molecules such as monoclonal antibodies) may decrease, inhibit or suspend T cell responses (from Fourgerolles et al. 1994, J. Exp. Med. 179: 619-29; Dustin, ml et al., 1986, J Immunol, 137: 245-54).

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The interaction of LFA-1 (consisting of CD1 la and CD18 subunits) with ICAM is necessary for the destruction of T cells, auxiliary T cell and B cell responses, natural destruction and antibody-dependent cytotoxicity. In addition, LFA-1 / ICAM interactions participate in the adhesion of leukocytes to endothelial cells, fibroblasts and epithelial cells, facilitating the migration of leukocytes from the vasculature to the sites of inflammation (Collins, T. 1995, Science and Medicine, 28 -37; Dustin, ML et al. 1991, Annual Rev Immunology,
9: 27-66).

The use of antibodies that interfere with LFA-1 / ICAM interactions decreases or inhibits the inflammatory process by blocking T cell activation and / or leukocyte extravasation. In vitro, monoclonal antibodies against LFA-1 or its ligands have inhibited T-cell activation (Kuypers, T. and Roos, D. 1989, Research in Immunology, 140: 461-86; Springer, TA, 1987, Annual Rev Immunology, 5: 223-52), T cell-dependent B-cell proliferation (Fischer, A. et al. 1986, J Immunol, 136: 3198-203), target cell lysis (Krensky, A. et al. 1983, J Immunol, 131: 6711-6) and T cell adhesion to vascular endothelium (Dustin, ML. Et al. 1988, Journal of Cell Biology, 107: 321-31). In mice, anti-CD11a antibodies have induced tolerance to protein antigens (Benjamin, R. et al., 1988, European Journal of Immunology, 18: 1079-88: Tanaka, Y. et al. 1995, European Journal of Immunology , 25: 1555-8), delayed the onset and reduced the severity of experimental autoimmune encephalomyelitis (Gordon, EJ et al. 1995, Journal of Neuroimmunology, 62: 153-60), inhibited the production of autoantibodies associated with lupus and prolonged the Survival of various types of tissue grafts (Cavazzana-Calco MS, Sarnacki S, Haddad E et al. Transplantation 1995; 59 (11): 1576-82; Nakakura EK, McCabe SM. Zheng B, Shorthouse RA et al. Transplantation 1993 ; 55 (2): 412-7; Connolly MK, Kitchens EA, Chan B et al., Clinical Immunology and Immunopathology 1994; 72 (2): 198-203; He Y, Mellon J, Apte R, Niederkom J. Investigative Ophthalmology and Visual Science 1994; 35 (8): 3218-25; Isobe M, Yagita H, Okumura K, Ihara A. Science 1992; 255: 1125-7; Kato Y, Yamataka A, Yagita H et al. Ann Surg nineteen ninety six; 223 (1): 94-100; Nishihara M, Gotoh M, Fukuzaki T et al. Transplantation Proceedings 1995; 27 (1): 372; Talent A, Nguyen M, Blake T et al., Transplantation 1993; 55 (2): 418-22; van Dijken PJ, Ghayur T, Mauch P et al. Transplantation 1990; 49 (5): 882-6). In clinical studies in humans it has been shown that murine anti-CD11a monoclonal antibodies help prevent graft failure after bone marrow transplantation (Cavazzana-Calco MS, Bordigoni P, Michel G et al. British Journal of Haematology 1996; 93 : 131-8; Fischer A, Friedrich W, Fasth A. Blood 1991; 77 (2): 249-56; Stoppa AM, Maraninchi D, Blaise D, Viens P et al. Transplant International 1991; 4: 3-7) and renal transplantation (Horamant M, Le Mauff B, Le Meur Y et al. Transplantation 1994; 58 (3): 377-80; Horamant M, Bedrossian J, Durand D et al. Transplantation 1996; 62 (11): 1565- 70; Le Mauff B, Horamant M, Rougier JP et al. Transplantation 1991; 52 (2): 291-6). An immunosuppressive drug that could reduce the incidence of both acute graft rejection and delayed graft function, while promoting long-term survival with minimal toxicity with the tolerance induction potential, would provide great benefits to the transplant field
renal.

There is still a need for new methods of administration of therapeutic compounds that reduces side effects and that increases the effectiveness of therapeutic compound

Summary of the Invention

An object of the present invention is provide uses related to an improved procedure of administration of a therapeutic compound. This and other objects will be apparent from the following description of allow embodiments that have been achieved by the invention.

The invention relates to a method for treat an LFA-1 mediated disorder by administering to a mammal in need thereof a first dose of conditioning or a compound that binds to the receptor of the surface of lymphocytes LFA-1; and later administer at least a second therapeutic dose of the compound, in which the second dose is higher than the first dose. The invention provides compounds for use in such a process, and related uses, as defined in the claims. He LFA-1 mediated disorder is psoriasis, and the compound is an anti-CD11a antibody in length complete subclass IgG1, as defined in the claims.

Other aspects of the invention will be apparent to from the following description of preferred embodiments that They are not intended to be limiting of the invention.

Brief description of the figures

Figure 1 shows the dosing schedule used in the study of Example 1. A indicates the time of the Global evaluation of the doctor and PASI, and skin biopsy.

Figure 2 shows the changes in the results of the PASI score by dose group for the study of Example 1. It is a summary of the change in percentage of the mean (+/- SD) in PASI scores from the initial level to the Days 28 and 56. * Subject 015 withdrew consent on Day 7 and there is no data for Days 28 and
56.

Figure 3 shows the response reduction at doses in the results of the PASI score for the study of Example 1.

Figure 4 shows the modulation of the levels of CD11a in lymphocytes and hu1124 in plasma for each of the A-E groups, for the study of Example 1.

Figure 5 summarizes histological data of the Example 1. Histological evidence of decrease of ICAM-1, keratin 16 (Ker 16) and CD11a expression in psoriatic plaques.

Figure 6 shows the decrease in acute adverse events with the time achieved in the Example 1 using the process of the invention. A Acute adverse event is one or more of fever (mild), headache (mild), nausea or vomiting within 24 hours of the dosage. A single patient may have had more than one event.

Figure 7A shows the amino acid sequence of the hu1124 light chain as shown in Fig 1A of WO98 / 23761.

Figure 7B shows the amino acid sequence of the heavy chain of hu1124 as shown in Fig 1B of WO98 / 23761.

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Definitions

The term "monoclonal antibody" as used herein refers to an antibody obtained from from a population of substantially homogeneous antibodies, it is that is, the individual antibodies that comprise the population are identical except for possible mutations that occur naturally they may be present in smaller amounts. The monoclonal antibodies are highly specific, being directed against a single antigenic site. In addition, unlike conventional antibody preparations (polyclonal) that normally include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directs against a single determinant on the antigen. In addition to his specificity, monoclonal antibodies are advantageous because they are synthesized by hybridoma culture without contaminating by other immunoglobulins The "monoclonal" modifier indicates that the character of the antibody has been obtained from a population of substantially homogeneous antibodies, and should not be interpreted as requiring the production of the antibody by any particular procedure For example, monoclonal antibodies to be used according to the present invention can be prepared by the hybridoma procedure first described by Kohler & Milstein, Nature, 256: 495 (1975), or can be prepared by recombinant DNA procedures (see, for example, the patent from the USA No. 4,816,567 (Cabilly et al.)).

In "chimeric" antibodies (immunoglobulins), a part of the heavy and / or light chain is identical to homologous sequences corresponding to antibodies derived from a particular species or belonging to a particular class or subclass of antibody, while the rest of the chain (s) is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another class or subclass of antibodies, provided they have the desired biological activity, for example, by binding to a receptor of the cell surface (U.S. Patent No. 4,816,567 (Cabilly et al.); and Morrison et al. Proc: Natl. Acad Sci. USA, 81: 6851-6855 (1984)). The hu1124 antibody is a humanized antibody. "Humanized" forms of non-human antibodies (eg, murine) are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab ', F (ab') 2 or other antibody sub-sequences antigen binding) containing a minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (receptor antibody) in which the residues of a receptor complementarity determining region (CDR) are replaced by residues of a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit that has the specificity, affinity and capacity desired. In some cases, the Fv structural region residues of the human immunoglobulin are replaced by corresponding non-human residues. In addition, the humanized antibody may comprise residues that are neither found in the recipient antibody nor in the imported CDR or structural region sequences. These modifications are made to further refine and optimize antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and usually two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are of a consensus sequence of human immunoglobulin. For more details see: Jones et al. Nature, 321: 522-525 (1986); Reichmann et al. Nature, 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596
(1992)).

Fv chain "antibody fragments single "or" sFv "comprise the domains V_ {H} and V_ {L} of antibody, in which these domains are present in a single polypeptide chain. Generally, the Fv polypeptide comprises furthermore a polypeptide linker between the VH domains and V_ {L} that allows the sFv to form the desired structure for the antigen binding. For a review of sFv see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, p. 269-315 (1994).

The term "diabody" refers to small antibody fragments with two binding sites to antigen whose fragments comprise a variable chain domain heavy (V_ {H}) connected to a light chain variable domain (V L) in the same polypeptide chain (V H and V L). Using a linker that is too short to allow mating between the two domains in the same chain is forced to that the domains pair with the complementary domains of another chain and create two antigen binding sites. The diabodies are described more fully in, for example, EP documents 404,097; WO 93/11161; and Hollinger et al. Proc. Natl Acad Sci. USA 90: 6444-6448 (1993).

The expression "linear antibodies" when used throughout this application refers to the antibodies described  in Zapata et al. Eng Protein 8 (10): 1057-1062 (1995). Briefly, these antibodies comprise a pair of tandem Fd segments (V_ {H} -C_ {H} 1-V_ {H} -C_ {1}) which form a pair of antigen binding regions. Antibodies linear can be bispecific or monospecific.

A "variant" antibody refers herein to a molecule that differs in the amino acid sequence from an amino acid sequence of the "main" antibody by virtue of the addition, deletion and / or substitution of one or more residue (s) of amino acid in the main antibody sequence. In the preferred embodiment, the variant comprises one or more amino acid substitution (ones) in one or more hypervariable region (s) of the main antibody. For example, the variant may comprise at least one, for example from about one to about ten, and preferably from about two to about five, substitutions in one or more hypervariable regions of the main antibody. Generally, the variant will have an amino acid sequence that has at least 75% amino acid sequence identity with the heavy or light chain variable domain sequences of the main antibody, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%. The identity or homology with respect to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical to the main antibody residues, after the sequences are aligned and spaces are introduced, if necessary, to achieve the maximum sequence identity in percentage. None of the N-terminus, C-terminus or internal extensions, deletions or insertions in the antibody sequence should be construed as affecting the identity or homology of the sequence. The variant retains the ability to bind the receptor and preferably has properties that are superior to those of the main antibody. For example, the variant may have a stronger binding affinity, enhanced capacity to activate the receptor, etc. To analyze such properties, for example, a Fab form of the variant antibody must be compared with a Fab form of the main antibody or a full length form of the variant antibody with respect to a full length form of the main antibody since it has been found that the form of the antibody affects its activity in the biological activity assay disclosed herein. The variant antibody of particular interest herein is one that shows at least about 10 times, preferably at least about 20 times, and most preferably at least about 50 times, of improvement in biological activity when compared to the antibody.
principal.

The term "modulate by decrease a cell surface receptor "means a procedure or method that reduces the number of molecules in the receptor on the surface of a cell type with respect to number of receptor molecules before the procedure or method For example, the administration of a therapeutic compound that binds to a surface receptor the cell will regulate by decreasing the receiver if the number of receptor molecules on the surface of the cell is smaller after administration than before administration of compound. The number of surface receptor molecules of the cell can be measured histologically using methods of known staining and counting.

A "conditioning dose" is a dose that attenuates or reduces the frequency or severity of the effects  Adverse side effects of the first dose associated with administration of a therapeutic compound. The dose of conditioning can be a therapeutic dose, a dose subtherapeutic, a symptomatic dose or a subsymptomatic dose. A therapeutic dose is a dose that has an effect therapeutic on the patient and a subtherapeutic dose is a dose that does not have a therapeutic effect on the patient treaty. A symptomatic dose is a dose that induces at least one adverse effect with administration and a subsymptomatic dose is a dose that does not induce an adverse effect.

The term "surface receptor of the cell "as used herein means any molecule shown on the surface of a cell and available to bind by therapeutic compounds that are put in contact with the cell surface. A molecule of the Such a cell surface is a "receptor" for the compound therapeutic.

The term "cell killing compound does not target "or a compound or ligand that" does not destroy "a cell population means a compound that binds to a cell surface receptor molecule, but that substantially does not reduce the number of cells in the population of cells. A non-destructive compound, for example, will reduce the number of cells in a population of cells approximately 50% or less, preferably about 30% or less, more preferably about 20% or less, based on the number of target cells in the cell population before contact or compound treatment.

The term "LFA-1 mediated disorders" refers to pathological conditions produced by cell adhesion interactions that involve the LFA-1 receptor on lymphocytes. The invention is limited to psoriasis, but other examples of such disorders include inflammatory T-cell responses such as inflammatory skin diseases other than psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult dysneic syndrome; dermatitis; meningitis; encephalitis; uveitis; allergic conditions such as eczema and asthma and other conditions that involve T-cell infiltration and chronic inflammatory response; hypersensitivity skin reactions (including dermatitis and urticaria); atherosclerosis; leukocyte adhesion deficiency; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen syndrome, type I diabetes and immune response associated with delayed cytokine-mediated hypersensitivity and T lymphocytes normally found in tuberculosis, sarcoidosis, polymyositis, granulomatosis and vasculitis; pernicious anemia, diseases that involve leukocyte diapedesis; CNS inflammatory disorder, multiorganic injury syndrome secondary to sepsis or trauma; autoimmune hemolytic anemia; myasthenia gravis; diseases mediated by the antigen-antibody complex; all types of transplant rejection that include graft versus host disease or graft host;
etc.

"Treat" a disease, disorder, cell condition or population includes therapy and treatment prophylactic for a short period of acute time and for a Long period of chronic time.

The term "mammal" refers to any animal classified as a mammal that includes beings humans, domestic and farm animals, and zoo animals, sports or pets such as dogs, horses, cats, cows, etc. Preferably, the mammal in this document is human.

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Detailed description of the preferred embodiments

It has now been discovered that a program of dosage in which a first conditioning dose of hu1124 antibody is followed by a second higher dose of the antibody is effective in conditioning a mammal to tolerate increasing or greater doses of the therapeutic antibody. This Dosing program allows to reduce the appearance of effects adverse events that occur from the initial administration and subsequent administrations of the therapeutic antibody, i.e. the invention reduces the adverse effects of the administration of the first dose and conditions the mammal for larger doses additional. Although some adverse effects will be observed like fever, headache, nausea, vomiting, breathing difficulties, myalgia, chills and changes in blood pressure, frequency and / or severity of these adverse effects is reduced surprisingly regarding administration using programs conventional dosing such as daily administration of equal doses of a therapeutic compound. Therefore the procedure of the present invention allows increasing the doses later and get the therapeutic benefits of higher doses of the therapeutic antibody while at the same time Minimizes the occurrence of adverse side effects.

In the invention, adverse side effects are reduced by providing a medicament for administering to a mammal a first conditioning dose of hu1124 antibody followed by a therapeutic dose. The term "therapeutic" in this context means that the compounds bind to the surface of the target cell and produce a change in the symptoms or condition associated with the disease or condition being treated. It is enough that a therapeutic dose produces a change with increases in the symptoms or conditions associated with the disease; A cure or complete remission of symptoms is not required. An expert in this field can easily determine whether a dose is therapeutic by establishing criteria to measure changes in symptoms or conditions of the disease being treated and then controlling the changes in these criteria according to known procedures. External physical conditions, histological examination of affected tissues in patients or the presence or absence of specific cells or compounds, which include a lesion, associated with a disease can provide objective criteria to assess the therapeutic effect. The invention is used to treat psoriasis in which the therapeutic effect is determined by a global evaluation of the patient's physician (EGM) and by scores of the severity index and area of psoriasis (PASI): a decrease in the PASI score indicates a therapeutic effect The activity of psoriatic disease can also be determined based on the global scale of lesion severity (GGL), percentage of total body surface area (ASC) affected by psoriasis, and plaque thickness.
psoriasis.

In the invention, the first dose is followed by a second dose that is higher than the first dose, that is, It contains a larger amount of therapeutic antibody. The first dose serves to condition the mammal to tolerate the second higher therapeutic dose In this way, the mammal can tolerate higher doses of the therapeutic antibody than they could be administered initially Therefore, within the scope of the present invention are additional doses that can be administered After the second dose. For example, within the use of the The present invention contemplates a third additional dose which is greater than or equal to the second dose and an additional fourth dose which is greater than or equal to the second or third dose.

In another embodiment, the first dose may repeat one or more times before giving the second dose higher. The first dose may be administered, for example, one, two or three times, most preferably only once before administered the second highest dose.

Doses can be administered according to any temporary schedule that is appropriate for the treatment of the disease or condition. For example, the dosages can be administered daily, weekly, biweekly or monthly in order to achieve the desired therapeutic effect and the reduction of adverse effects. Dosages can be administered before, during or after the development of the disorder. For example, to prevent rejection of host versus graft or graft versus host, the initial conditioning dose may be administered before, during or after the transplant occurs. The specific time schedule can easily be determined by a physician skilled in the administration of the therapeutic antibody by routine adjustments of the dosage schedule within the method of the present invention. The administration time of the first and second dosages, in addition to the subsequent dosages, will be adjusted to minimize adverse effects, while maintaining a maximum therapeutic effect. The occurrence of adverse effects can be controlled by routine interviews with the patient and adjusted to minimize the occurrence of side effects, in particular, fever, headache, nausea and / or vomiting by adjusting the dosage time. Any dosage time is considered to be within the scope of the present invention provided that the first conditioning dose of the antibody is administered followed by a second larger dose of the antibody. For example, additional doses may be in a daily or weekly schedule, followed by biweekly or monthly doses.
later.

The dosage amount can be determined easily using known dosage adjustment techniques by an expert doctor in the treatment of the disease or condition. The dosage amount will usually be found in a established therapeutic window for the therapeutic compound that will provide a therapeutic effect while minimizing the additional morbidity and mortality. Normally the compounds Therapeutics will be administered in a dosage ranging from 0.001 mg / kg and approximately 100 mg / kg per dose, preferably 0.1-20 mg / kg. The preferred dose of approximately 0.1-20 mg / kg is particularly useful for antibodies

Normally, the therapeutic antibody used in this invention is formulated by mixing it at room temperature at the appropriate pH and to the desired degree of purity with physiologically acceptable carriers, that is, vehicles that are non-toxic to the receptors at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of antagonist, but preferably ranges anywhere between about 3 and about 8. A suitable embodiment is the formulation at pH
6.0.

The anti-CD11a antibody for Use in this document is preferably sterile. Sterility can be easily achieved by filtration sterilization through membranes (0.2 micrometers). Preferably, the Peptides and therapeutic proteins are stored as solutions aqueous, although lyophilized formulations are acceptable for reconstitution.

The therapeutic antibody can be formulated, dosed and administered in a manner consistent with the good medical practice Factors to consider in this context include the particular disorder being treated, the particular mammal that is being treated, the clinical picture of the individual patient, the cause of the disorder, the agent's release site, the administration procedure, the temporary program of administration and other known factors for doctors general The "therapeutically effective amount" of the antibody  therapeutic to be administered will be governed by such considerations and is the minimum amount necessary to prevent, improve or treat psoriasis. Such amount is preferably less than the amount that is toxic to the host or makes the Host is significantly more susceptible to infections.

The therapeutic antibody can be administered. by any appropriate means that includes administration parenteral, subcutaneous, intraperitoneal, intrapulmonary, intranasal and intralesional. Parenteral infusions include administration intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous Preferably, the dosage is administered by injections, most preferably intravenous injections or subcutaneous, depending in part on whether the administration is brief or chronic

The invention relates to the treatment of psoriasis by administering to a mammal, preferably a human patient, in need of such a treatment a first conditioning dose of an anti-CD11a antibody; and administering a second therapeutic dose of the antibody, the second dose being greater than the first dose. The invention provides a related compound and use, as defined in the claims. This aspect of the invention is different from conventional dosing procedures for the treatment of such diseases that are generally treated with regularly spaced uniform doses of a therapeutic compound. For example, immunoadhesin LFA-3TIP, which is a recombinant dimeric protein consisting of the first extracellular domain of human LFA-3 fused to the hinge and regions of human IgG CH2 and CH3, has been administered in equal weekly doses of 0.005 mg / kg, 0.025 mg / kg, 0.050 mg / kg or 0.075 mg / kg. In a second study, patients received 0.05, 0.10 or 0.15 mg / kg in equal doses every four weeks (Kruegar et al.). In contrast, the invention provides a first conditioning dose and then a second therapeutic dose.
higher.

This dose programming procedure conditions the patient to tolerate higher doses of the therapeutic antibody that would be tolerated by the patient, particularly when there are adverse effects on the patients due to the administration of the therapeutic antibody. The first low dose of the process of the invention is useful for reducing fever, headache, nausea, vomiting etc., which frequently accompany an initial administration of a drug antibody. However, it is possible to prepare the medicament to administer a first low dose, within the scope of the invention, to patients who do not experience adverse effects with the first administration.
betrayal

The first dose conditions the patient to receive a second higher dose with a reduction in effects adverse effects that can be observed with higher doses of antibody therapeutic. Generally, as the amount of Dosage, also increases the number of adverse effects. The invention allows the administration of higher therapeutic doses more quickly and with less adverse effects. This improves the efficacy of therapy since the patient can tolerate doses older and for a longer time since there are minor effects unpleasant side

As described above, the amount of Dosage can be easily determined using techniques of Dosage adjustment known to a physician skilled in the Treatment of these diseases. The dosage amount is you will usually find inside a therapeutic window established for the therapeutic compound that will provide a therapeutic effect while minimizing morbidity and mortality additional. Normally, the therapeutic compounds are administered at a dosage ranging from 0.001 mg / kg and about 100 mg / kg per dose, preferably 0.1-20 mg / kg The preferred dose is particularly useful for compounds that contain antibodies.

The therapeutic compound for the treatment of a disease mediated by LFA-1 can be administered by any suitable means including parenteral, subcutaneous, intraperitoneal, intrapulmonary, intranasal and intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Preferably, the dosage is administered by injections, most preferably intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. As described above in more detail, the therapeutic compound for the treatment of a disease mediated by LFA-1 can be formulated, dosed and administered in a manner consistent with good practice.
medical

Psoriasis is an inflammatory disease characterized by keratinocyte hyperproliferation and accumulation of activated T cells in the epidermis and dermis of psoriatic lesions The regulation by increase of ICAM-1 in keratinocytes and their interaction with LFA-1 T-cells in lesional skin indicate that the treatment with an anti-CD11a antibody can interfere with the disease process in psoriasis.

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Examples

The process of the invention is exemplified. for the treatment of psoriasis (a disease mediated by LFA-1) with a therapeutic compound (an antibody) which binds to a cell surface receptor (CD11a). These examples also provide a representative example of Modulate by decreasing a cell surface receptor in a population of mammalian cells, reduce the effects secondary and conditioning a mammal to tolerate high doses of a therapeutic compound.

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Example one

Phase I multiple dose increase study of the effects of hu1124 in subjects with moderate to severe psoriasis (HUPS249)

The drug under study, hu1124, is an antibody known humanized anti-cD11a [see document WO 98/23761 (humanized MHM24 (Fab) -8); Werther WA et al. Humanization of an anti lymphocyte function-associated antigen (LFA) -1 monoclonal antibody and re-engineering of the humanized antibody for binding to rhesus LFA-1. J Immunol 1996; 157: 4986-95). hut1124 is a version of humanized IgG1 of a monoclonal antibody murine anti-CD1124a, MHM24, which recognizes CD11a Human and chimpanzee. The humanization of MHM24 was carried out grafting the murine complementarity that determines regions (hypervariable region) in heavy chain consensus sequences and slight human IgG1 / κ. For the V sequences of the H chain and L of hu 1124 refers to the GenBank registration number P_W62013 and P_W62017, respectively; the sequences also shown in Figure 1 in Werther et al. 1996, and in Fig. 1A and 1B in WO98 / 23761, incorporated herein by reference.

The study drug, hu1124, was supplied as a sterile, colorless, transparent, single-use solution in a glass vial. Each vial contained 10 ml of solution at a concentration of 4 mg / ml in 10 mM sodium acetate, pH 5.0, with 0.02% polysorbate 20, 0.1% trihydrated sodium acetate and 4% mannitol. No preservative was added to the solution. All the drug under study was stored at 2-8ºC (35.6-46.4ºF). The study drug was administered to subjects by continuous intravenous infusion for 90 minutes in a peripheral vein. The amount of drug that was administered was based on the weight and dosage group of the subject to whom the drug was assigned.
subject.

Security was assessed by events Adverse, clinical laboratory evaluations and vital signs Pre and post treatment. Immune activity was monitored by testing the effects on cell-mediated immunity reactions (delayed hypersensitivity), tetanus antibody responses and lymphocyte subpopulations (flow cytometry). Efficiency was monitored for changes in the clinical signs and symptoms of the disease (including the severity index and area of psoriasis. PASI scores) and global changes compared to the condition of initial level. Skin biopsies were studied for effects. of hu1124 on lymphocytes within psoriatic lesions. The Pharmacokinetics of the study drug was evaluated by controlling in series of plasma samples for hu 1124 during the 98 days after study start

Thirty-nine subjects with moderate to severe plaque psoriasis were included in eight study centers. Subjects included Caucasian, black, Asian and Hispanic subjects. The subjects 'ages ranged from 26 to 73 years, with only one subject over 70. The subjects' weight ranged between 65 and 122 kg. Between 15 and 72%, with a global median of 33%, of the body surface area was psoriatic in the subjects included in this study. Initial level PASI scores ranged from 15 to 42, with a global median of 23 for the 39 subjects in this study. Each of the 39 subjects received multiple doses of hu1124 ranging from 0.1 to 1.0 mg / kg administered by intravenous infusion. Of the 39 subjects, 10 were included in one of the 0.1 mg / kg dose groups (four in the 0.1 mg / kg dose group administered every two weeks and six in the 0.1 dose group mg / kg / week), 17 were included in the 0.3 mg / kg / week dose group, six were included in the 0.3-0.6 mg / kg / week dose group and six were included in the dose group of 0.3-1.0 mg / kg / week. All but five subjects completed the study. All subjects were evaluated for safety and efficacy. The following table shows the treatment program and the number of patients in each arm of the
study.

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TABLE 1 Dose increase (mg / kg) and schedule treatment

one

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Results - Security

The acute adverse events of the First dose were mainly fever (reported by 17/39 or 44% of subjects), headache (reported by 7/39 or 18% of subjects), nausea (reported by 5/39 or 13% of subjects) and vomiting (2/39 or 5% of subjects). Adverse events Acute (within 48 hours after dosing) of fever, headache or vomiting after the first dose is not reported in subjects who received 0.1 mg / kg every two weeks or weekly. Most acute adverse events They were of mild severity. And most importantly, the frequency of acute adverse events decreased with doses later in each dose group.

The multiple infusions of hul 124 were Safe and well tolerated by the subjects in this study. The incidence of overall decline in adverse events acute after the first dose in each dose group indicates that acute adverse events are the result of initial exposure to the drug and not the absolute level of the drug, which in turn indicates an adaptation or conditioning response to the "desensitizing" dosing program or "conditioner" of the invention.

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Results - Pharmacokinetics / Pharmacodynamics

The average peak and hul plasma levels 124 appeared to be dose dependent and increased as which increased the dose level of the medication under study. I dont know observed accumulation of hul 124 in the lower dose groups and observed a small degree of accumulation after infusing the maximum doses in the larger dose groups. One was observed decrease in the expression of CD11a within the term of 2-4 hours after administration of the study medication in all dose groups, noting a full recovery before the next dose in the groups of lower doses and within 7-10 days after that hu1124 levels decrease to low detection levels. In the two highest dose groups, hul binding sites 124 they remained saturated during the course of treatment.

A reversible increase in the number was observed average lymphocytes in the larger dose groups after Day 7 with a return to pretreatment numbers after the dosage is completed. With no dose were observed effects on the distribution of subtypes T and B or decreases in T cell subclasses.

The results of the antibody test tetanus indicated that a humoral antibody response established, especially an antibody response mediated by an IgG of a second set may persist in the presence of multiple doses of hu 1124. The antibody response was evaluated in 36 of the 39 patients using a double sandwich ELISA antigen. No antibody response detected anti-hu 1124 humans until Day 98 after multiple weekly doses

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Results - Efficiency

The effectiveness was based on the overall assessment of improvement, PASI scores and histological analysis of biopsies of skin. Some clinical improvement (ge little improvement) was observed in 76% (29/38) of the subjects on Day 56. Of the subjects that received at least 0.3 mg / kg / week, 64% (18/28) experienced a clinical improvement of at least passable. Five subjects experienced excellent improvement (i.e. 75-90% of improvement from the initial level), observing higher speeds of clinical improvement as the dose of the drug increased in study. Continuous improvement on Day 70 was observed in six subjects in the larger dose groups. Subjects infused with the higher doses of hu1124 had a greater decrease in their PASI scores compared to subjects infused with lower doses Ten subjects had a 50% decrease in their PASI scores. A dose response was observed as determined by the decrease in PASI scores in the groups of higher doses on Day 28; however, Day 56 was not detected Substantial differences between the larger dose groups. The histological analyzes of skin biopsies revealed a significant reduction in epidermal thickness and infiltration of T cells with clear anti-inflammatory effects and inversion of the pathological epidermal hyperplasia in subjects treated with at least 0.3 mg / kg / week.

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Conclusions

The conclusions of this infusion study increasing numbers of hu1124 in subjects with plaque psoriasis Moderate to severe are as follows:

(to)

hu1124 was safe and very tolerated in subjects that received multiple doses infused on the rise that oscillated between 0.1 mg / kg / every two weeks and 1.0 mg / kg / week;

(b)

hu1124 provided clinical improvement in most of subjects as measured by global assessments, scores PASI and histology;

(C)

hu1124 reduced levels of CD11a in lymphocytes in circulation;

(d)

h1124 did not affect an antibody response established humoral and did not elicit a response immune;

(and)

hu1124 did not reduce lymphocyte counts; the lymphocyte counts increased during dose treatment greater.

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Example 2

A study of increasing dose of single dose and multiple doses to assess the safety, pharmacokinetics and biological activity of hu1124 administered subcutaneously in subjects with psoriasis in moderate to severe plates (HUPS254)

This study evaluated the safety, pharmacokinetics and pharmacodynamics and the biological activity of hu1124 administered by subcutaneous injection in a single dose and in doses multiple to subjects with moderate to severe plaque psoriasis.

The drug under study, hu 1124, was the same as it was used in Example 1. It was supplied as single use vials containing 100 milligrams of freeze-dried drug free of sterile pyrogen containing hu1124 antibody at a concentration 100 mg / ml and 0.02 mmol of L-histidine, and 0.96 mmol of β, β-trehalose, pH 6.0, when reconstituted with 1.0 ml of sterile water for injection.

Twenty-six subjects received hu1124 subcutaneously The subjects in Group A (n = 2) received a single injection of 0.3 mg / kg of hu1124. The subjects in Groups B at E (n = 24) they received eight injections weekly in doses that they ranged between 0.5 and 2.0 mg / kg of hu1124.

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The following Table 2 shows the program of treatment and the number of patients in each arm of the study.

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TABLE 2 Dose increase and schedule treatment

2

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Adverse events were reported and evaluated in a similar way to Example 1. The events Acute adverse events included headache, fever, chills, myalgia, nausea and vomiting None of these adverse events that produced within 48 hours from the injection time with hu1124 was considered acute. Safety was assessed by examinations. pre and post treatment (including constant measurements vital), clinical laboratory evaluations (including analysis blood biochemists, hematology and urinalysis), by examining reported adverse clinical events and through an auditory evaluation. The effectiveness evaluation is based on EGM levels of improvements, changes in scores PASI and histological analysis of skin biopsies on Day 56.

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Results - Security

The subcutaneous administration of hu1124 has been Very well tolerated. No local skin reaction has been observed. It seemed that the incidence of acute adverse reactions (which produced within 48 hours) that were previously seen, after intravenous administration (Example 1, HUPS249), there were decreased by approximately 50%. The low incidence of headache (mild) in eight of 26 subjects (31%) and fever (fever) in two of 26  Subjects (8%) was notable. The use of the dosing schedule "desensitizer" or "conditioner" of the invention for dose administration has allowed administration safe up to 2 mg / kg with acute adverse events minima.

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Results - Efficiency

The study population was defined as subjects who had a history of and / or were considered for therapy systemic for moderate to severe chronic plaque psoriasis (BSA> 15% and PASI> 12) that had been diagnosed for at least six months and had been stable for at minus three months.

Based on the overall evaluation of the doctor (EGM) and decreases in the severity index score and area of psoriasis (PASI) a clear benefit of treatment with hu1124.

The improvement in psoriasis as judged by the EGM suggests a dose response. In Group A [dose group single (0.3 mg / kg)] no improvement was observed, as expected. The subjects in Groups B, C and D showed some improvement on the Day 56. The improvements were as follows: in Group B (0.5 mg / kg), 1 Excellent (75-99% improvement over the initial level), 1 Light (1-24% improvement), 2 Withdrawal; in Group C (0.5-1.0 mg / kg), 2 Good (50-74% improvement), 1 Passable (25-49% of improvement), 3 Light; in Group D (0.7-1.5 mg / kg), 1 Good, I Passable, 4 Light. The subjects in Group E They show the highest degree of improvement. In this group were 1 Excellent, 2 Good, 2 Passable, 2 Light, and I Withdrawn. The answer in Group E it indicates that all subjects dosed with hu1124 They showed some improvement (one subject withdrew on Day 7).

The severity and area index scores of psoriasis (PASI) decreased an average of 10.9% in the single dose group of 0.3 mg / kg, 47.1% in the 0.5 group mg / kg, 36.3% in the 0.5-1.0 mg / kg group, of 33.2% in the 0.7-1.5 mg / kg group and 35.6% in the 1.0-2.0 mg / kg group. In general, the higher be the EGM, the greater the reduction in the PASI score.

This study was subsequently extended to add 15 more subjects to Group C and 16 more to Group E. Therefore, the Group C had a final inclusion of 21 subjects and Group E had 24 subjects totaling 55 subjects included in 10 centers of study (the study of Group A was suspended).

Data generated from the total set of 55 subjects from the multiple dose groups showed the following results and observations. Substantial improvements were observed in EGM and PASI scores on Day 56. Of the 55 subjects in the multiple dose groups, 45% experienced good or better improvements in EGM (defined as an improvement of ≥ 50% of all signs). and clinical symptoms of psoriasis compared to the initial level) and 47% experienced at least a 50% decrease in PASI scores. In addition, 18% of these subjects experienced at least a 75% reduction in PASI scores on Day 56 and were categorized as patients responding to treatment. Among the multiple dose groups, higher proportions of subjects in the 0.5-1.0 mg / kg and 1.0-2.0 mg / kg groups experienced good or better improvements in EGM. To mention, a subject in the 1.0-2.0 mg / kg group experienced a complete resolution of disease symptoms as assessed by EGM. The highest proportions of subjects in these two dose groups also experienced at least 50% reductions in PASI scores compared to subjects in the other groups of
dose.

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Results - Summary

The administration of a subcutaneous formulation of hu1124 was well tolerated at the injection site. The clinical benefits were clearly observed with Passable, Good and Excellent (EGM) responses observed in several dosage groups. The most significant benefits were observed in particular in Group E (1.0-2.0 mg / kg), in which all dosed subjects (one subject was withdrawn) showed improvement already on Days 28-42 of
therapy.

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Example 3

A long-term multiple dose study for evaluate the safety, pharmacokinetics and biological activity of hu1124 administered intravenously and subcutaneously in subjects with moderate to severe plaque psoriasis (HUPS256)

In this study, two treatment groups receive multiple intravenous doses of hu1124 from 0.3 mg / kg to 1.0 mg / kg for 12 weeks. Each dose of hu1124 will be administered one once a week for a period of 90 minutes. Three groups of treatment receive multiple subcutaneous doses of hu1124 from 0.7 to 4.0 mg / kg, injected once a week for 12 weeks.

For intravenous administration, the drug under study, hu1124, is supplied as a pyrogen free solution, sterile, colorless, transparent, single use in a vial of glass. Each vial contains 10 ml of solution at a concentration 4 mg / ml in 10 mM sodium acetate, pH 5.0, with 20% polysorbate 0.02%, 0.1% trihydrate sodium acetate and 4% mannitol. I dont know add preservative to the solution. All the drug under study is Store at 2-8ºC (35.6-46.4ºF). For subcutaneous administration, the drug under study is supplied as single-use vials containing 100 milligrams of freeze-dried sterile pyrogen free medicine hu1124 antibody at a concentration of 100 mg / ml and 0.02 mmol of L-histidine, and 0.96 mmol of β, β-trehalose, pH 6.0, when reconstitute with 1.0 ml of sterile water for injection.

The following Table 3 shows the program of treatment and the number of patients in each arm of the study.

TABLE 3 Treatment program

4

Safety is assessed by pre and post-treatment exams (including vital sign measurements), hearing evaluations, clinical laboratory evaluations (including biochemical blood tests, hematology and urine tests), antibody against hu1124 (HAHA) and by Examination of adverse clinical events reported as in the previous examples. Pharmacokinetics are evaluated using various ex vivo immunological assays. Biological activity is evaluated by changes in PASI.

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Results

To date, 61 patients and the Dosage has been well tolerated in all doses used in the study. An adverse event of local reaction has been reported of the skin among the 40 patients who have received SC doses of up to 2.0 mg / kg None of the 18 patients who have received doses SC of up to 4.0 mg / kg has reported an adverse event of local skin reaction. The clinical benefits are seen as Passable, Good and Excellent (EGM) responses. To date, the anti-CD11a (hu1124) administered by SC injection It seems to be safe, well tolerated and has biological activity and promising clinic.

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Example 4

Phase III study of efficacy, safety and tolerability of subcutaneous administration of hu1124 in subjects with psoriasis in Moderate to severe plaques during three phases: first treatment, retreatment and prolonged treatment (ACD2058g)

Subjects received 12 weekly doses of anti-CD11a (hu1124) or placebo administered by SC injection as explained briefly in the program table Dosage immediately below. The doses are consisting of an initial conditioning dose at a concentration of 0.7 mg / kg SC and weekly dose of 1.0 mg / kg administered SC or 2.0 mg / kg SC after this.

TABLE 4 Dosing Program

5

Anti-CD11a is supplied (hu1124) as in the previous Examples 2 and 3. When reconstituted with 1.0 ml of sterile water for injection (SWFI), each vial contains hu1124 at a concentration of 100 mg / ml, in addition to polysorbate 20, L-histidine hydrochloride and β, β-trehalose, at pH 6.0.

The determinations of primary efficacy are they do on PT Day 84, which is at the end of the first period treatment (PT). On PT Day 84, subjects are defined as patients who respond, patients who respond partially or patients who do not respond according to the following definitions: patient who responds: PASI has decreased ≥75% since PT Day 0; partially responding patient: PASI has decreased ≥50% but <75% since PT Day 0; unresponsive patient: PASI has decreased <50% since PT Day 0.

This response to therapy determines whether subjects are assigned to a period of observation (OB) or treatment  prolonged (TP) after completing PT Day assessments 84. Subjects defined as responding patients enter the observation period (OB) and are followed well for 6 months or until they relapse, whichever comes first. The relapse is defined as the loss of 50% or more of the improvement in PASI achieved between PT Day 0 and PT Day 84 (see Section 4.5.3.a). At the time of relapse, the subjects who received active drug during the period of first treatment (PT) enter in the retreat period (RT) and re-randomized in a 2: 1 ratio to anti-CD11a or placebo, respectively. Subjects who received placebo during the period of first treatment (PT) and were classified as patients respondents receive anti-CD11a during the period of retreatment Despite the re-randomization, the subjects remain within the dose level group (high dose or dose low) assigned during the first treatment period (PT). During the retreat period (RT), subjects receive a second course of treatment consisting of 12 SC injections weekly.

The subjects defined as patients who respond partially or patients who do not respond at the end of First treatment period (PT) were assigned to the period of prolonged treatment (TP). The subjects remain within the dose levels assigned in the first treatment period (PT). Subjects who had received anti-CD11a in the First treatment period (PT) is re-randomized 2: 1 to anti-CD11a or placebo, respectively. All the subjects who received placebo in the first treatment period (PT) are assigned to anti-CD11a within their level of dose. TP Day 0 occurs on the same day as PT Day 84; from there of the two drug treatment courses under study be continuous for a period of 24 weeks.

In a related study (ACD2062g), subjects who had previously received treatment with anti-CD11a and they had antibodies to anti-CD11a and the subjects they are receiving simultaneous topical therapy of psoriasis or light phototherapy Ultraviolet B (UVB) are treated with the same dosage schedule shown in the preceding table.

Efficiency, safety and tolerability are measured as described in the previous examples.

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Results

The previous dosage schedule with doses of Initial minor conditioning is very tolerated. The benefits clinicians are observed with Passable, Good and Excellent responses (EGM).

The use of the invention provides greater therapeutic index than conventional and current therapy minimizing Toxicity and adverse side effects.

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Claims (10)

1. Use of an antibody full-length anti-CD11a of subclass IgG1 in the preparation of a medicine for the treatment of psoriasis whose treatment includes administering to a mammal a first dose of antibody conditioning followed by a second therapeutic dose of the antibody, in which the second therapeutic dose is higher than the first dose, and in which the antibody is the hu1124 antibody that has V chain sequences light and heavy as shown in figures 7A and 7B respectively. 2. Use of claim 1, comprising also administer a third therapeutic dose, in which the third dose is higher than the second dose. 3. Use of claim 2, comprising also administer a fourth therapeutic dose, in which the Fourth dose is greater than or equal to the third dose. 4. Use of any one of the claims 1 to 3, in which the administration is intravenous or subcutaneous. 5. Use of any one of the claims 1 to 4, in which the administration is not more than once per week. 6. Anti-CD11a antibody full length of subclass IgG1 for use in a procedure of psoriasis treatment whose treatment includes administering to a mammal a first dose of antibody conditioning followed by a second therapeutic dose of the antibody, in which the second therapeutic dose is higher than the first dose, and in which antibody is the hu1124 antibody that has V sequences Light and heavy chain as shown in Figures 7A and 7B respectively. 7. Anti-CD11a antibody claim 6, wherein the treatment further comprises administer a third therapeutic dose, in which the third dose is higher than the second dose. 8. Anti-CD11a antibody claim 7, wherein the treatment further comprises administer a fourth therapeutic dose, in which the fourth dose is greater than or equal to the third dose. 9. Anti-CD11a antibody of one any of claims 6 to 8, wherein the Administration is intravenous or subcutaneous. 10. Anti-CD11a antibody of one any one of claims 6 to 9, wherein the Administration is not more than once a week.